Catheter flush solution and method for its use

ABSTRACT

A solution of the present invention useful for flushing an intravascular catheter includes a pharmacologically acceptable sodium salt, a pharmacologically acceptable calcium salt, a pharmacologically acceptable potassium salt and about one milligram per milliliter polyhexamethylene biguanide hydrochloride in an aqueous admixture. Additionally, the solution of the invention may also contain a pharmacologically acceptable salt of lactic acid.

FIELD OF INVENTION

The present invention is generally related to intravascular cathetersand more particularly to a solution useful for maintaining the patencyof a long-term indwelling intravascular catheter and a method for itsuse.

BACKGROUND

Intravascular catheters are among the most commonly used medicaldevices. Such catheters are routinely placed into a patient's vascularsystem for many procedures and often are left in place for extendedperiods. Since an intravascular catheter is a direct path from theoutside environment to the patient's bloodstream, the catheter'spresence presents a substantial and continuous potential forintroduction of microorganisms into the patient's bloodstream.Practitioners have developed many protocols related to placement, use,attachment and detachment of fluid handling devices and other proceduresrelated to catheters. The goal of almost all of these procedures is toavoid introduction of a microorganism into the patient's bloodstream.When a medicament is introduced into a patient through a catheter, thepractitioner commonly follows the introduction with a flush solutionthat may include an anticoagulant such as heparin. The purpose of theflush solution is to move the medicament out of the catheter so that theentire dosage is delivered, and to leave a residual fill in the catheterso that the patient's blood does not back up in the catheter andpossibly form a clot that would occlude the bore of the catheter. Thus,when the catheter is subsequently needed again, the properly flushedcatheter is likely fully patent and ready for the next usage.

In 1988, Root, et al., published a study that reported on the effect ofdisodium ethylene diamine tetra acetic acid (EDTA), a compound wellknown for its chelating properties in vivo and widely used as ananticoagulant in vitro. The authors compared EDTA, heparin andvancomycin/heparin for effectiveness upon the growth of S. epidermis invitro and its relation to infection prophylaxis of Hickman catheters intheir report in Antimicrob. Agents Chemother., 32:1627-1631, 1988.Recently, Raad, et al. in U.S. Pat. No. 5,363,754 disclosed thatpharmaceutical compositions of a mixture of minocycline and EDTA wereuseful in maintaining the patency of a catheter port. More recently,Raad, et al. in U.S. Pat. No. 5,688,516 further disclosed that effectivecatheter flush solutions could be prepared with non-glycopeptideantimicrobial agents other than vancomycin and a second agent selectedform the group consisting of: (a) an anticoagulant, (b) anantithrombotic agent and (c) a chelating agent selected from a group ofchelating agents. Raad, et al. teaches that since many antibiotic agentsare not particularly stable at ambient conditions in aqueous solutions,that the disclosed compositions are stable and effective for about onemonth when stored under refrigerated conditions and that the solutionshould be brought to room temperature before administration to apatient. Alternatively, Raad, et al. teaches a kit including threecompartments, the compartments containing the antimicrobial agent, thechelating, anticoagulant or antithrombotic agent and a diluent such assaline, Ringers solution or water so that the practitioner could mix thecomponents prior to administration to the patient, thereby avoiding thereported stability problems.

While the disclosures of Raad, et al. teach a series of antimicrobialagents with a variety of other compounds, given the tendency ofmicroorganisms to develop resistance to many antibiotic agents and thesensitivity to many people to certain antibiotics and other compounds,there still is a need for a catheter flush solution that does notinclude an antibiotic, is stable under ambient storage conditions andcontains only materials with little likelihood of inducing an allergicresponse in a sensitive patient. Such a solution is disclosedhereinbelow.

SUMMARY

A solution of the present invention useful for flushing an intravascularcatheter includes a pharmacologically acceptable sodium salt, apharmacologically acceptable calcium salt, a pharmacologicallyacceptable potassium salt and about one milligram per milliliterpolyhexamethylene biguanide hydrochloride in an aqueous admixture.Additionally, the solution of the invention may also contain apharmacologically acceptable salt of lactic acid.

The catheter flush solution of the invention, when compared under invitro simulated use conditions to a known catheter flush solutioncomposed of minocycline and ethylenediaamine tetra acetic acid (M-EDTA),suprisingly showed similar results in activity against microorganisms inestablished biofilms. Additionally, unlike the M-EDTA, which is stablefor about one month under refrigeration, the catheter flush solution ofthe invention retains full activity even after autoclave sterilizationor ultra filtration. The catheter flush solution of the invention issimple to prepare, is thermally stable and has acceptable toxicityproperties consistent with its intended use.

DETAILED DESCRIPTION

While this invention is satisfied by embodiments in many differentforms, herein described in detail preferred embodiments of the inventionwith the understanding that the present disclosure is to be consideredexemplary of the principles of the invention and is not intended tolimit the invention to the embodiments described.

A solution of the present invention useful for flushing an intravascularcatheter includes a pharmacologically acceptable sodium salt such assodium chloride or the like in a concentration of between about 820 mgto about 900 mg, a pharmacologically acceptable calcium salt, such ascalcium chloride dihydrate or the like in a concentration between about30.0 mg to about 36.0 mg, a pharmacologically acceptable potassium salt,such as potassium chloride or the like in a concentration between about28.5 to about 31.5 mg and about one milligram per milliliterpolyhexamethylene biguanide hydrochloride in an aqueous admixture withone hundred milliliters of water for injection U.S.P. For particularapplications, the solution of the invention may also include sodiumlactate in a concentration between about 290 mg and about 330 mg in theone hundred milliliter aqueous admixture.

The solution of the invention is preferably exposed to conditions thatsubstantially render any microorganisms therein non-viable and packagedin a sealed vessel, such as a syringe, septum-closed vial or an ampoulethat is substantially resistant to the passage of microorganisms.Preferably, the sealed vessel contains an aliquot of the flush solutionthat is sufficient to perform one catheter flush procedure. Forparticular applications, a bulk vessel may be preferred that contains asufficient amount of the solution to dispense multiple aliquots forindividual catheter flush procedures.

An in vitro comparison between the catheter flush solution containingsodium lactate of the invention and a catheter flush solution disclosedin U.S. Pat. No. 5,362,754 including minocycline and ethylene diaaminetetraacetic acid (M-EDTA) was conducted. The results of this evaluationof the two solutions' activity on tubing that had P. aeruginosa inestablished biofilms suprisingly showed that the catheter flush solutionof the invention performed similarly to the M-EDTA solution disclosed inU.S. Pat. No. 5,362,754. Table I lists the variables used in thecomparison and the results. In this comparison, segments of test tubingwere incubated in trypticase soy broth (TSB) containing P. aeruginosa toacquire a loading in the tubing bore of the biofilm containing themicroorganism. The tubing segments were recovered from the broth andattached to syringes containing the catheter flush solutions. The testsolutions were injected into the tubing segments with the syringe andallowed to stand at ambient conditions. At the times indicated, thesolutions were withdrawn from the particular segments of tubing, thetubing bore washed with sterile saline and the saline was culturedproviding the results in the table. In this comparison, the flushsolution of the invention included sodium lactate in the concentrationas described above.

TABLE I Colony forming units (CFU) Time elapsed recovered/cm² of (hours)Tubing Material Test solution tubing 0 Silicone None (control) >9,500 0Polyvinylchloride None (control) >15,000 3 Silicone 5,362,754 >9,500 3Silicone Invention >9,500 3 Polyvinylchloride 5,362,754 <15 3Polyvinylchloride Invention <15 5 Silicone 5,362,754 <9.5 5 SiliconeInvention 9,500 5 Polyvinylchloride 5,362,754 <15 5 PolyvinylchlorideInvention <15 24 Silicone 5,362,754 13 24 Silicone Invention 9.5 24Polyvinylchloride 5,362,754 <15 24 Polyvinylchloride Invention <15

Established biofilms are difficult to eradicate and the bacteriaestablished in these films are resistant to conventional antibiotictreatment. The flush solution of U.S. Pat. No. 5,362,754 has been shownto be effective in preventing device related infections, partially orcompletely due to its effect on biofilms and the bacteria in thesefilms.

Additionally, a comparison of the minimum inhibitory concentration (MIC)of the solution of the invention after filter sterilization and aftersteam sterilization following a widely accepted protocol in anautoclave. The flush solutions of the invention showed no difference inthe MIC between the filter sterilized by passage of the solution througha 0.22 micron filter and the steam sterilized solution of the inventionagainst S. aureus, P. aeruginosa, E. Coli and C. albicans. The stabilityof the flush solution to steam sterilization suggests that the long termshelf stability at ambient temperatures of prepackaged unit dosealiquots of the solution should be at least two years, although this isyet to be confirmed.

A method for flushing an intravenous catheter includes providing anadmixed solution substantially free of microorganisms containing betweenabout 820 mg to about 900 mg of sodium chloride, between about 28.5 toabout 31.5 mg of potassium chloride, between about 30.0 to about 36.0calcium chloride dihydrate, about 100 mg polyhexamethylene biguanidehydrochloride in one hundred milliters of water for injection U.S.P. Thesolution of the invention preferably includes between about 290 mg toabout 330 mg of sodium lactate. The method includes filling a fluidhandling device, preferably a syringe, with an aliquot of the solutionsufficient to perform a catheter flush procedure. The preferred amountfor the flush procedure is generally about two or three milliliters. Thepractitioner then attaches the syringe to the target intravascularcatheter that requires flushing and administers the solution into thecatheter, thereby completing the flush procedure. The frequency of theperformance of the procedure may be once daily or, for particularsituations, more or less frequently.

Toxicity studies of the preferred catheter flush solution of theinvention containing sodium lactate show that at doses of thepolyhexamethylene biguanide hydrochloride at up to one time, ten times,fifty times and seventy times the expected dose level (two ml flush in aseventy kg. Human) level, there was no significantly greater biologicalreactivity compared to controls. Toxicity studies of the preferredcatheter flush solution at eighty five times (lowest observable acuteeffect level), one hundred times, and two hundred times the expecteddose level, there was slight to moderate biological reactivity comparedto controls. At a dosage level of one thousand times the expected dosagelevel, there was significantly greater reactivity compared to controls.

The pharmacologically acceptable salts used in the preparation of theflush solution of the invention, i.e. sodium chloride, calcium chloridedihydrate, potassium chloride and sodium lactate are widely available.Any source of these materials meeting the requirements of the UnitedStates Pharmacopeia (U.S.P.) are satisfactory. The same is true for thewater for injection U.S.P. Any water that meets the requirements listedin the U.S.P. for water for injection is satisfactory for use in theinvention.

Polyhexamethylene biguanide hydrochloride with a molecular formula ofC₈H₁₈N₅Cl(C₈H₁₈N₅Cl)_(n) is a polymeric material with a molecular weightbetween about 1800 and about 2400 and is available as a twenty percentaqueous solution from Zeneca, Wilmington, Del. as Cosmocil® CQ. Thecompound has high activity against a wide range of microorganisms, ithas very low mammalian toxicity and is chemically stable. The compoundis widely used as a preservative in cleaning solutions for contactlenses. Polyhexamethylene biguanide hydrochloride is also referred to aspolyaminopropyl biguanide by the Cosmetic Toiletries and FragrancesAssociation (CTFA) who recognize its use as a preservative in water inoil and oil in water emulsions and as a antimicrobial agent in surgicalscrubs.

The pharmacologically acceptable salts and the water for injectionU.S.P. portion of the solution of the invention substantiallycorresponds to the U.S.P. formulation for Ringer's solution and LactatedRinger's solution. This portion is well recognized as a benign vehiclefor intravenous infusion. The addition of the polyhexamethylenebiguanide hydrochloride at the level disclosed herein suprisinglyrenders the solution substantially as capable of eliminatingmicroorganisms present in established biofilms as the combination of theM-EDTA of the art. Unlike the previous catheter flush solution of theart, the catheter flush solution of the invention exhibits good thermalstability, a property that makes it suitable for packaging inready-to-use unit dose kits capable of being stored at ambientconditions.

What is claimed is:
 1. A solution useful for flushing an intravascularcatheter and having activity against microorganisms in establishedbiofilms consisting essentially of: a pharmacologically acceptablesodium salt, a pharmacologically acceptable calcium salt, apharmacologically acceptable potassium salt and about one gram permilliliter polyhexamethylene biguanide in aqueous admixture.
 2. Thecatheter flush solution of claim 1 wherein said pharmacologicallyacceptable sodium salt is sodium chloride, said pharmacologicallyacceptable calcium salt is calcium chloride and said pharmacologicallyacceptable potassium salt is potassium chloride.
 3. The catheter flushsolution of claim 2 wherein said sodium chloride is present in aconcentration between about 820 mg to about 900 mg, said potassiumchloride is present in a concentration between about 28.5 mg to about31.5 mg and said calcium chloride is present in a concentration betweenabout 30.0 to about 36.0 mg as the dihydrate in one hundred millilitersof water.
 4. The solution of claim 3 further comprising sodium lactate.5. The solution of claim 4 wherein said sodium lactate is present in aconcentration between about 290 mg and about 330 mg in said one hundredmilliliters of water for injection U.S.P.
 6. The solution of claim 1being sealed in a package resistant to the passage of microorganisms andexposed to thermal energy sufficient to render any microorganism thereinnon-viable.
 7. The solution of claim 1 being passed through a filterhaving a pore size sufficient to substantially remove any microorganismpresent therein and sealed in a suitable package substantially free ofand resistant to the passage of microorganisms.
 8. A solution useful forflushing an intravascular catheter and having activity againstmicroorganisms in established biofilms consisting essentially of anadmixture of sodium chloride in a concentration between about 820 mg toabout 900 mg, potassium chloride in a concentration between about 28.5mg to about 31.5 mg , calcium chloride in a concentration between about30.0 to about 36.0 mg as the dihydrate and about 100 mg ofpolyhexamethylene biguanide in one hundred milliliters of water.
 9. Thesolution of claim 8 further comprising said solution being exposed toconditions capable of rendering any microorganisms therein substantiallynon-viable and wherein aliquots of said solution are sealed in a fluidhandling device suitable for administration of said solution into aintravascular catheter disposed in a patient.
 10. The solution of claim8 further comprising sodium lactate in a concentration between about 290mg and about 330 mg in said aqueous admixture.